The Effect of Intraocular Haloperidol on Motor Function in Models of Two Neuropsychiatric Disorders: Implications for the Origin and Treatment of Parkinson’s Disease, Psychosis and Drug Addiction

<b>Background:</b> It has recently been proposed that the retina plays an important modulatory role in the control of motor function that is usually attributed exclusively to the function of the nigro-striatal dopamine (NSD) system. Indeed, it has been proposed further that Parkinson's disease (PD) begins in and progresses from the retina and may be effectively treated from there. While previous intraocular work has employed intravitreal (IVIT) administration of toxins to induce experimental PD, the first study series reported here examines the effect of IVIT haloperidol on motor performance while the second study examines the effect of IVIT haloperidol on the unilateral rotation model of PD, both in a circadian context. <b>Methods:</b> Motor tests included open field performance and the latency to perform three motor tests after the IVIT injection of haloperidol with and without amphetamine pretreatment. In a second study, IVIT injections of the melatonin antagonist ML-23 or L-dopa were made after unilateral lesions of the NSD in rats that were placed in a rotometer examining spontaneous ipsilateral and contralateral turning. <b>Results:</b> IVIT haloperidol produced robust changes in several motor parameters during the light and dark phase of the LD cycle which were enhanced by amphetamine pretreatment. In the second study, while IVIT L-dopa had only a minor effect on spontaneous rotation during the light phase, IVIT haloperidol produced a robust effect upon ipsilateral turning. The reduction in spontaneous ipsilateral turning was seen after IVIT injections into the eye ipsilateral or contralateral to the hemisphere in which NSD destruction occurred. Reduced turning was seen during both the light and dark phases of the L/D cycle. <b>Conclusions:</b> These results illustrate that IVIT injections of DA and melatonin receptor antagonists can differentially alter motor function via the retina. This suggests that the retina may be a treatment target not only for PD but also for other DA- and melatonin-mediated disorders such as drug addiction, psychosis and schizophrenia.